title: SET7/9-dependent methylation of ARTD1 at K508 stimulates poly-ADP-ribose formation after oxidative stress.
abstract: ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly PARP1) is localized in the nucleus, where it ADP-ribosylates specific target proteins. The post-translational modification (PTM) with a single ADP-ribose unit or with polymeric ADP-ribose (PAR) chains regulates protein function as well as protein-protein interactions and is implicated in many biological processes and diseases. SET7/9 (Setd7, KMT7) is a protein methyltransferase that catalyses lysine monomethylation of histones, but also methylates many non-histone target proteins such as p53 or DNMT1. Here, we identify ARTD1 as a new SET7/9 target protein that is methylated at K508 in vitro and in vivo. ARTD1 auto-modification inhibits its methylation by SET7/9, while auto-poly-ADP-ribosylation is not impaired by prior methylation of ARTD1. Moreover, ARTD1 methylation by SET7/9 enhances the synthesis of PAR upon oxidative stress in vivo. Furthermore, laser irradiation-induced PAR formation and ARTD1 recruitment to sites of DNA damage in a SET7/9-dependent manner. Together, these results reveal a novel mechanism for the regulation of cellular ARTD1 activity by SET7/9 to assure efficient PAR formation upon cellular stress.
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kassner
authors.forename: Anneli
authors.initials: A
authors.lastname: Andersson
authors.forename: Monika
authors.initials: M
authors.lastname: Fey
authors.forename: Martin
authors.initials: M
authors.lastname: Tomas
authors.forename: Elisa
authors.initials: E
authors.lastname: Ferrando-May
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004249:DNA Damage; D019175:DNA Methylation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D016297:Mutagenesis, Site-Directed; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones; D011064:Poly Adenosine Diphosphate Ribose; D011495:Histone-Lysine N-Methyltransferase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: ADP-ribosylation; PARP-1; SET7/9; lysine methylation; protein regulation